EP4201948A1 - Procédé de préparation de dérivés d'acide 1-(n-(quinoléine-2-yl)-(phénylamino)-1-désoxy-bêta-d-glucopyranuronique - Google Patents

Procédé de préparation de dérivés d'acide 1-(n-(quinoléine-2-yl)-(phénylamino)-1-désoxy-bêta-d-glucopyranuronique Download PDF

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Publication number
EP4201948A1
EP4201948A1 EP21306866.1A EP21306866A EP4201948A1 EP 4201948 A1 EP4201948 A1 EP 4201948A1 EP 21306866 A EP21306866 A EP 21306866A EP 4201948 A1 EP4201948 A1 EP 4201948A1
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EP
European Patent Office
Prior art keywords
compound
formula
group
alkyl
purification
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP21306866.1A
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German (de)
English (en)
Inventor
Sébastien Rose
Guillaume Magueur
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Abivax SA
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Abivax SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Abivax SA filed Critical Abivax SA
Priority to EP21306866.1A priority Critical patent/EP4201948A1/fr
Priority to AU2022419092A priority patent/AU2022419092A1/en
Priority to MX2024007736A priority patent/MX2024007736A/es
Priority to KR1020247024312A priority patent/KR20240125013A/ko
Priority to US18/722,995 priority patent/US20250145651A1/en
Priority to IL313723A priority patent/IL313723A/en
Priority to EP22840666.6A priority patent/EP4452991A1/fr
Priority to PCT/EP2022/086874 priority patent/WO2023118061A1/fr
Priority to CN202280090477.6A priority patent/CN118804920A/zh
Priority to CA3241742A priority patent/CA3241742A1/fr
Priority to JP2024537814A priority patent/JP2024545967A/ja
Publication of EP4201948A1 publication Critical patent/EP4201948A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/02—Heterocyclic radicals containing only nitrogen as ring hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C07H1/06—Separation; Purification

Definitions

  • WO 2016/135052 application describes the preparation and the use of quinoline-2-yl-phenylamine glucuronide derivative.
  • Said glucuronide derivative is a N-glucuronide metabolite of chloro-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine, also named ABX464.
  • Said compound is disclosed as being useful in the treatment or prevention of viral or retroviral infection and virus-related conditions, in particular AIDS or an AIDS-related condition or Human Immunodeficiency virus (HIV). It has further been disclosed as being useful in the treatment of various inflammatory diseases in WO2020/127843 .
  • ABX464 is a drug candidate under clinical trials in the treatment of moderate to severe ulcerative colitis (UC).
  • UC ulcerative colitis
  • a route of synthesis of the glucuronide derivative is disclosed in WO2016/135052 according to the route of synthesis as depicted below wherein said compound (4) is also disclosed as a new intermediate compound.
  • the purification step as disclosed in WO2016/135052 i.e. extraction with ethyl acetate of the crude compound (1), followed by a concentration to dryness to afford a solid extract, is not compliant with the industrial scale. Indeed, it is not desirable implementing a concentration to dryness after said extraction and even not feasible to deal with solid extracts at an industrial scale.
  • the inventors have in other words stated that scale-up generated purification issues.
  • the inventors have surprisingly found specific conditions for purifying the crude quinolinyl-2-yl-phenylalamine glucuronide derivatives of formula (I) as defined herein after, in particular obtained after a deprotection step of compound (IV) as defined herein after.
  • the inventors have in particular developed means for purifying said derivatives of formula (I) starting from a solution phase and not from a solid extract.
  • the present invention is additionally intended to provide a method for preparing quinolinyl-2-yl-phenylalamine glucuronide derivatives of formula (I) as defined herein after, which is improved in the perspective of an industrial-scale mass production.
  • the inventors have in particular simplified various aspects as it will be more apparent in the following description, which globally renders the claimed process perfectly compliant with the industrial scale.
  • ambient temperature or “room temperature” refers to a temperature ranging from 15°C to 30°C, more particularly from 18°C to 25°C.
  • the isolation of the desired product is achieved through precipitation, which may be followed by a purification step on silica gel chromatography column, itself optionally preceded by a silica gel pre-treatment.
  • R, n, R' and n' have the following meanings:
  • R, n, R' and n' have the following meanings:
  • the compound of formula (I) is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Examples are, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
  • the purification step as disclosed in WO2016/135052 consists in an extraction step with ethyl acetate of the crude compound (1) after having quenched the reaction mixture which is then acidified, followed by an extraction with ethyl acetate and a drying step on sodium sulfate and at last purification on silica column of the solid extract obtained after having removed the solvent.
  • the drying step may be performed at a temperature ranging from 20 to 30°C.
  • the crude compound of formula (I), and in particular crude compound (1), in particular the reaction mixture obtained after a deprotection step of compound (IV) as defined herein after, can therefore be diluted with methanol, and after the addition over cold water, a brown solid precipitate may be obtained.
  • ICH level requirement for methanol is under 3000 ppm with respect to the total amount of the desired compound.
  • ICH level requirement for tetrahydrofuran is 720 ppm with respect to the total amount of the desired compound.
  • ICH level requirement for toluene is 890 ppm with respect to the total amount of the desired compound.
  • ICH level requirement for methylene chloride is 600 ppm with respect to the total amount of the desired compound.
  • a process of purification of a crude compound of formula (I) as defined above wherein it is preceded by a purification step on silica gel column, optionally preceded by a silica gel pre-treatment.
  • said compound of formula (I) as defined above is adsorbed onto the silica gel.
  • Said optional preliminary stage of purification allows avoiding having a greater number of runs on the silica gel column for obtaining the compound of formula (I).
  • Said silica gel pre-treatment also presents the advantage of allowing to gather the unreacted compound of formula (II), in particular of formula (2), which may be reused for further manufacturing batches for preparing derivatives of formula (I), in particular of formula (1).
  • Silica gel may be washed at a first time with a solvent selected from methylene chloride, tetrahydrofuran or mixture thereof.
  • the number of washes of these first series of washes may vary between 1 and 3.
  • the product may then be desorbed with a second washing sequence with only THF or only methanol.
  • the number of washes of these second series of washes may vary between 1 and 3.
  • the silica gel column may in particular be selected from normal phase and in particular from silica gel "Chromatorex GS60-20/45".
  • the elution may be performed with a methylene chloride/methanol mixture.
  • the purification step as described above allows obtaining a compound of formula (I) presenting good quality properties and namely a high purity, and also presenting acceptable levels of residual solvents.
  • the starting compound of formula (II) may be cited as well as the methyl ester having the following formula (V) which for compound (1) is compound (5)
  • the compound of formula (I) obtained according to the present invention may typically present a purity ranging from 90 to 97%, in particular from 92 to 96%, and even more particularly from 93 to 96%, with an amount of compound of formula (II), in particular compound (2) ranging from 0.3 to 2.1% and an amount of impurity of formula (V), in particular impurity (5) ranging from 1.9 to 2.3%.
  • the compound of formula (I) obtained according to the present invention may typically present residual content of methanol inferior to 750ppm, methylene chloride inferior to 420ppm, tetrahydrofuran inferior to 360ppm and toluene inferior to 445ppm.
  • the present process of purification may be carried out after a deprotection step of a compound of formula (IV) (IV), wherein R, R', n, n' and R" are as defined above, as more detailed herein after as step 2.
  • Compound of formula (IV) may be prepared by reacting a compound of formula (II) with a compound of formula (II) (III), wherein R" is as defined above, according to a Koenigs-Knorr synthesis as more detailed herein after as step 1.
  • step 1 differs from said coupling step as disclosed in WO2016/135052 mainly by the introduction of the compound of formula (III) in solution and with a fractional introduction.
  • step 1 may be implemented by reacting compound of formula (II) with compound of formula (III) as defined above, in the presence of CdCO 3 , in a solvent selected from aromatic solvents, such as toluene or xylene, more particularly in toluene.
  • the reaction may be performed at reflux temperature, i.e. at 111°C.
  • the inventors have moreover stated that a fractional introduction of the compound of formula (III) in solution allowed to improve the reaction conversion.
  • step 1 may be carried out with a fractional introduction of the compound of formula (III) in solution, in particular of compound (3), in particular in two parts.
  • a first introduction may be performed with a molar ratio of compound of formula (III) with respect to the compound of formula (II), in particular of compound (3) with respect to compound (2), ranging from 0.6 to 1, in particular ranging from 0.7 to 0.9
  • a second introduction may be performed with a molar ratio of compound of formula (III) with respect to the compound of formula (II), in particular of compound (3) with respect to compound (2), ranging from 0.6 to 1, in particular ranging from 0.7 to 0.9, with a total molar ratio with respect to compound of formula (II) ranging from 1.2 to 2, in particular from 1.4 to 1.8.
  • Step 1 may be carried out for 10 to 120 hours, in particular for 20 to 80 hours, and even more particularly for 30 to 50 hours.
  • Example 1.1 more particularly illustrates said step 1.
  • step 2 differs from the deprotection step as disclosed in WO2016/135052 mainly by the removal of hydrogen peroxide. Said removal presents an advantage in terms of security of the process.
  • the present step 2 does not need anymore the use of sodium thiosulfate.
  • solvent volumes such as of THF and of water may be decreased.
  • the solvent may be implemented in a volume ratio with respect to compound of formula (IV) ranging from 5 to 30, in particular from 5 to 15, more particularly from 5 to 7.
  • Yield at this stage of the manufacturing process i.e. after the purification step, including the hereabove described pre-treatment on silica gel, the purification on silica gel column and the precipitation step as described above, may range from 10% to 20%, in particular from 12% to 17%.
  • Example 1.2 more particularly illustrates said step 2.
  • R" is a methyl group.
  • the compound of formula (II) is compound (2) (2)
  • the compound of formula (III) is compound (3)
  • Example 1 Manufacturing process for preparing crude compound (1)
  • a compound (2) as defined above (20.0g) was mixed with cadmium carbonate (6.0g, 0.6 eq) and toluene (580mL, 29 volumes). The resulting mixture was azeotropically dried for 1h before compound (3) as defined above (38.0g, 1.6 eq.) was added in four portions over 28h onto the refluxing mixture. The mixture was heated at reflux for an additional period of 46h before being cooled down to room temperature, filtered and rinsed with methylene chloride. Filtrates were joined and concentrated to dryness before being diluted in DCM, washed 3 times with water, dried over sodium sulfate, concentrated to dryness and diluted in THF before being engaged in step 2.
  • Said compound (2) (65.0kg) was mixed with cadmium carbonate (52.7kg, 1.6 eq) and toluene (325L, 5 volumes). The resulting mixture was heated to reflux for azeotropic drying and a solution of compound (3) (61.1kg, 0.8 eq.) in toluene (318.5L, 2.5 volumes) was added at this temperature over 8h. Partial distillation of toluene (160L, 2.5 vol) was performed and the reflux was maintained during the night (10h). The second part of the solution of compound (3) (61.1kg, 0.8 eq.) in toluene (318.5L, 2.5 volumes) was added at reflux over 8.5h.
  • Said compound (4) in THF solution resulting from step 1 (310kg of solution, 126kg of (4)) was diluted with tetrahydrofuran (449kg).
  • a solution of lithium hydroxide monohydrate (80.6kg) in water (327L) was added at 20°C onto the compound (4) solution and stirred for 2h at 20°C.
  • Aqueous layer was discarded and the organic layer was concentrated, diluted with water (252L) and methylene chloride (670kg) and acidified until pH 1 with hydrochloric acid.
  • the organic layer was separated and the aqueous layer extracted with DCM (335kg). Organic layers were joined and washed with water (252L).
  • silica gel (90.8kg) was added to the organic layer, the mixture stirred for 30min at 20°C, filtered and the silica gel pad washed with methylene chloride (168kg) and twice with a mixture of DCM (160kg) and THF (6.2L). These three washes were joined for a further valorisation of unreacted compound (2).
  • the silica gel pad was then washed successively with 112kg and 2x56kg of THF.
  • the resulting solution was concentrated under vacuum and the residue diluted in a mixture of DCM (67kg) and THF (1.3L).
  • the resulting solution was purified by silica gel chromatography with a DCM/methanol mixture as eluant. Collected fractions were gathered, concentrated under vacuum and diluted in 1 volume of methanol (15L) with respect to estimated amount of compound (1).
  • a precipitation of crude compound (1) as produced in example 1 is performed as follows.
  • Said crude compound (1) (15kg) diluted in 1 vol of methanol (15L) from example 1 was then added on 20 volumes of demineralised water (300L) at 0/5°C over 1 hour and rinsed with 0.5 volume of methanol. The suspension was filtered and the cake washed with demineralised water (15L). The wet product was dried in tray oven at 30°C until water content and residual solvents were meeting the specifications. The obtained product was a brown solid obtained with 95% of yield (14.35kg).
  • Compound (1) obtained according to the present protocol have a 95.3% HPLC purity and contains 0.8% of compound (2) and 2.0% of methyl ester impurity (5). Water content was 3.5% and residual solvents were as follow: methanol ⁇ 750ppm, DCM ⁇ 150ppm, THF ⁇ 180ppm and toluene ⁇ 223pm.
  • the purification step performed according to the present invention has been observed as being completely compliant with the industrial scale, and affords compound (1), under an amorphous solid form, respecting the ICH Residual solvents requirements of the European Medicines Agency.
  • a part partitioned as in example 2.1 above was dried at 30°C for 100h and at 50°C during 11 hours.
  • the obtained product was a brown solid with an HPLC purity of 93.4% and contains 2.1% of compound (2) and 2.1% of methyl ester impurity (5).
  • the purification step performed according to a process outside the present invention i.e. with a temperature above 30°C
  • a precipitation of crude compound (1) as produced in example 1 is performed as follows.
  • Said crude compound (1) is solubilized (1.4g) with 4 vol of DCM and 0.6 vol of THF to obtain a solution.
  • Said solution is added onto 10 vol of heptane (with 0.5 of IPA) over 1h45 at 20-25°C, and then rinsed with 0.5 vol of DCM.
  • the mixture is then stirred for 2h30 at room temperature. Filtration of the fluid suspension is then carried out and washed with 4 ⁇ 0.5 vol of heptane to give 0.856 g of wet brown product.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
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EP21306866.1A 2021-12-21 2021-12-21 Procédé de préparation de dérivés d'acide 1-(n-(quinoléine-2-yl)-(phénylamino)-1-désoxy-bêta-d-glucopyranuronique Withdrawn EP4201948A1 (fr)

Priority Applications (11)

Application Number Priority Date Filing Date Title
EP21306866.1A EP4201948A1 (fr) 2021-12-21 2021-12-21 Procédé de préparation de dérivés d'acide 1-(n-(quinoléine-2-yl)-(phénylamino)-1-désoxy-bêta-d-glucopyranuronique
AU2022419092A AU2022419092A1 (en) 2021-12-21 2022-12-20 Method of preparation of 1-(n-(quinolin-2-yl)- (phenylamino)-1-deoxy-βeta-d-glucopyranuronic acid derivatives
MX2024007736A MX2024007736A (es) 2021-12-21 2022-12-20 Metodo de preparacion de derivados del acido 1-(n-(quinolin-2-il)- (fenilamino)-1-desoxi-beta-d-glucopiranuronico.
KR1020247024312A KR20240125013A (ko) 2021-12-21 2022-12-20 1-(n-(퀴놀린-2-일)-(페닐아미노)-1-데옥시-베타-d-글루코피라누론산유도체의 제조 방법
US18/722,995 US20250145651A1 (en) 2021-12-21 2022-12-20 Method of preparation of 1-(n-(quinolin-2-yl)-(phenylamino)-1-deoxy-beta-d-glucopyranuronic acid derivatives
IL313723A IL313723A (en) 2021-12-21 2022-12-20 Method of preparation of 1-(n-(quinolin-2-yl)- (phenylamino)-1-deoxy-βeta-d-glucopyranuronic acid derivatives
EP22840666.6A EP4452991A1 (fr) 2021-12-21 2022-12-20 Procédé de préparation de dérivés d'acide 1-(n-(quinolin-2-yl)-(phénylamino)-1-désoxy-beta-d-glucopyranuronique
PCT/EP2022/086874 WO2023118061A1 (fr) 2021-12-21 2022-12-20 Procédé de préparation de dérivés d'acide 1-(n-(quinolin-2-yl)-(phénylamino)-1-désoxy-βeta-d-glucopyranuronique
CN202280090477.6A CN118804920A (zh) 2021-12-21 2022-12-20 1-(N-(喹啉-2-基)-(苯基氨基)-1-脱氧-β-D-吡喃葡糖醛酸衍生物的制备方法
CA3241742A CA3241742A1 (fr) 2021-12-21 2022-12-20 Procede de preparation de derives d'acide 1-(n-(quinolin-2-yl)-(phenylamino)-1-desoxy-beta-d-glucopyranuronique
JP2024537814A JP2024545967A (ja) 2021-12-21 2022-12-20 １－（ｎ－（キノリン－２－イル）－（フェニルアミノ）－１－デオキシ－ベータ－ｄ－グルコピラヌロン酸誘導体の調製の方法

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
EP21306866.1A EP4201948A1 (fr) 2021-12-21 2021-12-21 Procédé de préparation de dérivés d'acide 1-(n-(quinoléine-2-yl)-(phénylamino)-1-désoxy-bêta-d-glucopyranuronique

Publications (1)

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EP4201948A1 true EP4201948A1 (fr) 2023-06-28

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Application Number Title Priority Date Filing Date
EP21306866.1A Withdrawn EP4201948A1 (fr) 2021-12-21 2021-12-21 Procédé de préparation de dérivés d'acide 1-(n-(quinoléine-2-yl)-(phénylamino)-1-désoxy-bêta-d-glucopyranuronique
EP22840666.6A Pending EP4452991A1 (fr) 2021-12-21 2022-12-20 Procédé de préparation de dérivés d'acide 1-(n-(quinolin-2-yl)-(phénylamino)-1-désoxy-beta-d-glucopyranuronique

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EP22840666.6A Pending EP4452991A1 (fr) 2021-12-21 2022-12-20 Procédé de préparation de dérivés d'acide 1-(n-(quinolin-2-yl)-(phénylamino)-1-désoxy-beta-d-glucopyranuronique

Country Status (10)

Country Link
US (1) US20250145651A1 (fr)
EP (2) EP4201948A1 (fr)
JP (1) JP2024545967A (fr)
KR (1) KR20240125013A (fr)
CN (1) CN118804920A (fr)
AU (1) AU2022419092A1 (fr)
CA (1) CA3241742A1 (fr)
IL (1) IL313723A (fr)
MX (1) MX2024007736A (fr)
WO (1) WO2023118061A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016135052A1 (fr) 2015-02-23 2016-09-01 Abivax Nouveau dérivé de quinoléine destiné à être utilisé dans le traitement et la prévention des infections virales
WO2020127843A1 (fr) 2018-12-20 2020-06-25 Abivax Dérivés de quinoléine destinés à être utilisés dans le traitement de maladies inflammatoires

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016135052A1 (fr) 2015-02-23 2016-09-01 Abivax Nouveau dérivé de quinoléine destiné à être utilisé dans le traitement et la prévention des infections virales
WO2020127843A1 (fr) 2018-12-20 2020-06-25 Abivax Dérivés de quinoléine destinés à être utilisés dans le traitement de maladies inflammatoires

Also Published As

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JP2024545967A (ja) 2024-12-16
MX2024007736A (es) 2024-07-02
US20250145651A1 (en) 2025-05-08
CN118804920A (zh) 2024-10-18
EP4452991A1 (fr) 2024-10-30
WO2023118061A1 (fr) 2023-06-29
KR20240125013A (ko) 2024-08-19
IL313723A (en) 2024-08-01
AU2022419092A1 (en) 2024-07-11
CA3241742A1 (fr) 2023-06-29

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